Rosacea is strongly associated with melanoma in Caucasians

Rosacea is often considered a cosmetic problem but is known to be associated with a variety of comorbidities. To identify such risks, we generated two age- and sex-matched real-world cohorts of 122,444 patients each with and without rosacea. In contrast to earlier studies, we found significant associations with malignant melanoma (OR 6.02, 95% CI 5.76–6.32). This association does not exist for an Asian sub-cohort, which could explain previous inconclusive or conflicting reports. Several strongly associated comorbidities like visual disturbances (ICD-10: H53–H54; OR 4.80, 4.68–4.92), metabolic disorders (E73–E79; OR 3.17, 3.11–3.22), joint problems (M25; OR 4.16, 4.08–4.25) and type 2 diabetes (E11; OR 1.62, 1.58–1.65) should be watched as a risk for rosacea patients. Rosacea is associated with some comorbidities and ethnicity may be a risk factor in melanoma development. The retrospective nature of this study and the sole use of ICD-10 code based filtering calls for future validation of our findings. Additionally, confounding factors such as skin type and previous UV exposure should be included in future studies.


Statistics
We used TriNetX analytics tools for propensity score matching, compare outcome analysis and Kaplan-Meier survival analysis.After obtaining the baseline medial records including age, sex and diagnoses, we filtered for patients with and without rosacea (L71) using the ICD-10 code based system.To allow comparison between the two disparaging groups, we used propensity score matching for 1:1 matching of patients based on age and sex.After matching, we investigated comorbidities previously linked to rosacea (Table 1).We calculated the Risk Difference, Risk Ratio and Odds Ratio of these comorbidities in our cohorts with and without rosacea.Furthermore, we executed Kaplan-Meier analysis specifically for malignant melanoma.The primary outcome in this analysis was median survival, which was defined as the number of days when survival dropped below 50%.Additionally, we carried out Log-Rank and Proportionality testing and calculated the Hazard Ratio.Risk analysis included outcomes and comorbidities prior and after the index event, while Kaplan-Meier survival Table 1.Comorbidities analyzed in patients with or without rosacea.ICD-10: international Classification of Diseases 10. www.nature.com/scientificreports/analysis excluded patients with an outcome prior to the time window starting one day after the index event and ending five years after the index event.

Results
We received the medical health record of 132,388 patients with a L71-diagnosis (+ rosacea) and 21,780,847 patients without a L71-diagnosis (-rosacea).Data inquiry, allocation and propensity score matching using the TriNetX database are shown in a consolidated standard of reporting trial (CONSORT) flow (inquiry on June 5th, 2023) (see Fig. 1).After propensity score matching, both cohorts consisted of 122,444 patients.Each cohort consisted of 84,752 female subjects (69.2% of study population) and 37,692 male subjects (30.8% of study population).Due to matching, age did not vary significantly in the cohorts, with a mean age of 55.5 at index event (see Table 2).

Rosacea is associated with an increased risk of malignant melanoma and systemic diseases
After propensity score matching, we determined the risk of multiple systemic diseases in both our cohorts, that have previously been associated to rosacea 8 (see Table 3).While the risk of being diagnosed with a vascular disease was at 0.185 in patients without rosacea, this risk increased to 0.336 in patients with rosacea [OR 2.234  With the starkly increased risk for malignant melanoma in our rosacea population, we performed a Kaplan-Meier analysis of this subset of patients.15,056 patients in cohort 1 (w/rosacea) and 1752 patients in cohort 2 w/o rosacea were excluded from this analysis, as they were diagnosed with malignant melanoma before their rosacea diagnosis.The survival probability at the end of the time window was 92.51% and 97.71% for the cohort with or without rosacea, respectively.At an HR of 3.286 (95% CI 3.101, 3.481), the mortality of malignant melanoma patients was higher if they also suffered from rosacea (p = 0.059).

Rosacea is not a risk factor for malignant melanoma in Asian populations
As previous studies in Asian populations have shown no association of rosacea and malignant melanoma 23 , we analyzed this sub-cohort separately.After adding the demographic parameter, we received the medical records of 470,834 patients.Of these, 1494 (0.31%) had received the diagnosis of rosacea, while 469,340 (99.68%) had not.Data inquiry, allocation and propensity score matching using the TriNetX database are shown in a consolidated standard of reporting trial (CONSORT) flow (inquiry on July 24th, 2023) (see Fig. 2).After propensity score matching, both cohorts consisted of 1494 patients.The cohorts then contained 1109 (74.23%) female and 475 (31.79%) male patients with an average age of 45.9 years (see Table 4).In the Asian subpopulation, both cohorts had 10 events of malignant melanoma, leading to a risk of 0.007 of being diagnosed with malignant melanoma both with and without rosacea.Hence, there was no risk difference and an OR of 1 (0.415, 2.410) (see Table 5).

Discussion
The aim of this study was to gain unbiased insight into a possible association of rosacea and systemic diseases on a global level using the rea-world database TriNetX.Here, we were able to show an association not only to metabolic disease, type 2 diabetes, joint problems and ophthalmologic disease, but were able to identify a strong association of rosacea and malignant melanoma as well.When viewed separately from other demographics, our Asian sub-cohort showed no association of rosacea and malignant melanoma, which is in accordance with previous data from Asian working groups 23,24 .
In their 2022 study, Cho et al. investigated the association between rosacea and different subtypes of skin cancer in a nationwide cohort study 23 .Using the data of 11,420 patients collected over nine years in Korea, they were able to show an increased risk of actinic keratosis and keratinocytic carcinoma in rosacea patients.While the Incidence Risk Ratio (IRR) for skin cancer in general was statistically significant in rosacea patients at 2.61 (95% CI 1.60-4.28),this was not the case when regarding malignant melanoma separately [IRR 1.19 (0.28-4.97)].A possible explanation for this lack of association of malignant melanoma and rosacea in this Korean population could lie in the differing distribution pattern of malignant melanoma in Korean patients.While superficial spreading melanoma and nodular melanoma make up 70% and 20% of diagnosed melanoma cases in patients   www.nature.com/scientificreports/ of European descent respectively 25 , acral melanoma has been shown to be the most commonly diagnosed form of melanoma for Korean, Taiwanese and Chinese patients [26][27][28] .Not only is this subtype of melanoma not characterized by UV-radiation induced mutations as commonly found in other subtypes, but is it commonly found in the lower regions of the body, nailbeds and palms, regions not commonly affected by rosacea 29,30 .Additionally, rosacea is often underdiagnosed in patients with non-white skin, as the discerning of efflorescences such erythema and teleangiectasias often proves to be difficult 31 .This highlights the need for a more differentiated regard of ethnicity as a factor in medical research.
In this study, we were able to identify a strong association of rosacea and malignant melanoma in Caucasian patients.Our findings stand in contrast to those gathered in Denmark by Egeberg et al. 4 .In their Danish nationwide cohort study of 49,475 rosacea patients and 4,312,213 subjects of the general Danish population, Egeberg et al. analyzed the risk for cancer in patients with rosacea.Here, they discovered a significant association between rosacea and non-melanoma skin cancer, though not for malignant melanoma.Additionally, rosacea was associated with a higher risk of basal cell carcinoma, but not malignant melanoma in the American Nurses' Health Study II carried out from 1989 to 2011 32 .In their 2023 systemic review on the association of rosacea and malignancies, Thapa et al. 33 were able to determine an increased risk of non-melanoma skin cancer in rosacea patient, though no significant association with melanoma could be found.Taken together, the contrasts in our findings stress the limitations of observational studies and the need for further investigations into the association of rosacea and all subtypes of skin cancers.
Observational studies have identified a plethora of comorbidities linked to rosacea.Not only is there evidence suggesting increased incidence of inflammatory bowel disease and cardiovascular diseases, but also metabolic diseases such as dyslipidemia and diabetes 8 .In our study, we were able to further validate these association.Additionally, we were able to determine an increased risk of ophthalmologic disease including blepharitis and disease of the lacrimal duct.As up to 72% of rosacea patients are estimated to suffer from ocular symptoms and corneal ulcers due to ocular rosacea can deeply impact vision 34 , we hypothesize that the increased number of ophthalmologic diseases in our cohort could be a reflection of the high percentage of ocular rosacea.These findings underline the importance of interdisciplinary cooperation in the treatment rosacea.
Due to the retrospective nature of our study, certain limitations apply to its interpretation.As the TriNetX database allows filtering based on ICD codes provided in medical health records, this does not directly imply a medically confirmed diagnosis.This filtering disregards different subtypes and severities of rosacea as well as important prognostic factors in malignant melanoma, such as Breslow's depth or melanoma subtypes.Moreover, there was no given information on lifestyle factors such as UV exposure, both a trigger for rosacea exacerbation and the development of skin cancers such as malignant melanoma 2,16 .Even though this study included a global patient population, the data requires a cautious interpretation, as it allows only for the detection of correlations, not causative relationships.While the database incorporates different ethnicities, it is dominated by a Caucasian population, a population commonly affected by rosacea.This limits the transferability of this data on a global level.Nevertheless, the novel association of rosacea and malignant melanoma warrants further investigation.
In the last decades, screenings for early detection of malignant melanoma have been controversially discussed.While there have been differing opinions on the socio-economic cost of skin cancer screenings and overtreatment of malignant melanoma, studies support the potential benefit of screening 35 .Not only is an early diagnosis of melanoma crucial for therapy as it is decisive for TNM staging and corresponding survival rates 36 , but the rising cost of skin cancer treatment is an economic burden that highlights the need for early detection and skin cancer prevention 13 .Additionally, UV radiation is not only a main contributor in the development of melanoma and non melanoma skin cancer, but also a known trigger and hypothesized to be crucial to rosacea pathogenesis 37,38 .Given the correlation of malignant melanoma and rosacea as well as the increased mortality of rosacea patients with concomitant melanoma in our study, the importance of UV avoidance or protection should not be underrepresented in consultation of rosacea patients.
In conclusion, we were able to determine an increased risk of joint problems, metabolic disease, visual disturbances, type 2 diabetes and malignant melanoma in rosacea patients.While rosacea has been previously linked to an increased risk of systemic diseases, our findings regarding malignant melanoma contrast with the findings of past studies.These differences highlight the need for further investigation of the possible connection of these two dermatologic diseases. https://doi.org/10.1038/s41598-024-62552-8

Figure 1 .
Figure 1.CONSORT flow diagram of data inquiry for patients with and without rosacea (L71).Major stages indicated in blue boxes.ICD-10: International Classification of Diseases 10, L71: rosacea.

Figure 2 .
Figure 2. CONSORT flow diagram of data inquiry for patients with and without rosacea (L71) in Asian subcohort.Major stages indicated in blue boxes.ICD-10: International Classification of Diseases 10, L71: rosacea.

Table 2 .
Inquiry results and propensity score matching of patients with and without rosacea.Cohort 1: patients with inpatient encounter and ICD-10 diagnosis of L71, Cohort 2: patients with inpatient encounter and no ICD-10 L71-diagnosis.ICD-10: International Classification of Diseases 10.

matching After matching Patients (n) Cohort 1 w/Rosacea Cohort 2 w/o Rosacea p-value Standardized mean difference Cohort 1 w/Rosacea Cohort 2 w/o Rosacea p-value Standardized mean difference
Vol:.(1234567890) Scientific Reports | (2024) 14:11949 | https://doi.org/10.1038/s41598-024-62552-8www.nature.com/scientificreports/(2.192, 2.276)].The Risk Difference for heart disease lay at 0.108, with an OR of 1.649 (1.621, 1.677) for patients with rosacea.Similarly, the OR of type 2 diabetes was 1.618 (1.584, 1.652), with an increased risk in rosacea patients.The risk of metabolic diseases was severely increased in patients with rosacea, with 56,082 rosacea patients of the 122,444 cohort having been diagnosed with metabolic diseases, while only 25,801 patients without rosacea had diagnosed metabolic diseases [OR 3.165 (3.110, 3.222)].Joint disease and ophthalmologic disease as well were more prevalent in our rosacea cohort [joint disease: OR 4.164 (4.083, 4.246), ophthalmologic disease: OR 4.801 (4.681, 4.924)].Surprisingly, malignant melanoma and other skin neoplasms were the comorbidity most strongly associated with rosacea.Though 2192 patients without rosacea had been diagnosed with a malignant skin cancer, 12,128 of the 122,444 rosacea patients had concomitant skin cancer, making up approximately 10% of the study population [OR 6.031 (5.759, 6.316)].In a subset analysis of rosacea patients with neoplasms of the skin, we were able to determine not only an increased risk of non-melanoma skin cancer [C44; OR 5.550 (5.345, 5.763)], but of malignant melanoma (C43) as well [OR 4.468 (4.144, 4.818)].

Table 3 .
Summary of rosacea comorbidities in cohort 1 and cohort 2.

Table 4 .
Inquiry results of Asian sub-cohort with and w/o rosacea.Cohort 1: Asian patients with inpatient encounter and ICD-10 diagnosis of L71, Cohort 2: Asian patients with inpatient encounter and no ICD-10 L71-diagnosis.ICD-10: International Classification of Diseases 10.